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From: TSS ()
Subject: The Genetic Approach to Controlling BSE
Date: September 13, 2006 at 9:35 am PST

The Genetic Approach to Controlling BSE

By: David A. Rodger

Stephen Moore was on holiday in his native

Australia back in May 2003, when he received

the telephone call that changed his life. “A Canadian

reporter was on the line asking me to

comment on a case of bovine spongiform encephalopathy

(BSE) in Alberta,” says Dr.

Moore “I still don’t know how he tracked me

down. There wasn’t much I could say because,

of course, this was news to me.”

Back in Edmonton, where he is Chair of Bovine

Genomics in the University of Alberta’s

Department of Agricultural, Food and Nutritional

Science, Dr. Moore was quickly brought

up to date. He and his research group had

been intimately involved in mapping the bovine

genome and were considered leaders in identifying

and characterizing genes that affect cattle

growth, yield, fat content and meat tenderness.

“There’s a genetic component in BSE susceptibility,”

he explains. “You only have to look at

the UK where some animals in a herd came

down with the disease while others didn’t.

This was despite their having eaten the same

contaminated feed. What are the genetic factors

that render cattle more susceptible or

more resistant to BSE? The answers will help

us with intervention, diagnosis, and treatment.”

In January 2006, the Alberta Prion Research

Institute appointed Dr. Moore its first scientific

director. Dr. Moore also leads PrioNet’s Research

Theme I on BSE. He is Principal Investigator

on two APRI-PrioNet co-funded projects ...2

BSE

- one related to BSE and the other to Chronic Wasting

Disease. Other partners include the University of Alberta,

National Microbiology Laboratories - Public

Health Agency of Canada, National Centre for Foreign

Animal Disease - Canadian Food Inspection Agency.

“The only place in the world that has had a statistically

significant number of BSE cases is the UK,” he says.

“The number in Canada is, thankfully, too few for genetic

analysis. So, two of my students went to the

Rosslyn Institute in Scotland to extract DNA from the

blood samples gathered from BSE-infected cattle. That

trip was necessary because blood samples are infectious

and can’t be brought into Canada, while DNA

samples are harmless and can be imported. We’re now

analyzing the DNA.”

In late July 2006, another case of BSE was discovered,

involving a 50-month old Alberta dairy cow born long

after Canada’s ban on the use of cattle parts in cattle

feed. How close is a test that detects BSE and other

TSEs in live healthy animals? When will we be able to

detect them in live animals as opposed to postmortem?

“Before there can be a valid test - dozens are in trials

now - two issues must be resolved,” says Dr. Moore.

“First, it must be easy to collect a sample, and second,

it can’t cost too much. If the test costs more than the

animal is worth, it’s of little benefit to producers.” For

more information visit the Alberta Prion Research

Institute web site at www.prioninstitute.ca. •

Coming to terms with Chronic Wasting disease

By: David A. Rodger

PrioNet’s Scientific Director, Neil Cashman,

has referred to chronic wasting disease

(CWD) as “the threat in our own backyard.”

Indeed, it could be the Transmissible

Spongiform Encephalopathy with the greatest

potential for species devastation. Leading

PrioNet’s Theme 2 efforts to understand and

control CWD is Ted Leighton of the Western

College of Veterinary Medicine in Saskatoon.

Dr. Leighton is recognized internationally for

his research into wildlife diseases. So it will

surprise many to discover that he did his

undergraduate work at Cornell University not

in science but in Theatre Arts. “Theatre Arts

had liberal course requirements,” he explains,

“enabling me to take natural science, social

science and humanities in a mix that provided

an excellent general education.” He received

his veterinary degree from the University of

Saskatchewan in 1979, completed a Ph.D. in

veterinary pathology at Cornell in 1984, and

returned to the University of Saskatchewan

later that year as professor of veterinary

pathology.

Currently Dr. Leighton is Executive Director

of the Canadian Cooperative Wildlife Health

Centre, which is headquartered in Saskatoon.

The organization is a partnership among

Canada’s veterinary colleges and government

agencies responsible for wildlife management,

agriculture, and public health. The Centre’s

mandate is one of disease surveillance. It has

programs to monitor the occurrence and

spread of such diseases as avian influenza,

West Nile virus, and CWD (since 1997).

CWD on elk farms in Saskatchewan and

Alberta has been eradicated through a

systematic program of culling infected or

exposed animals. Unfortunately, CWD in wild

animals, especially white-tailed and mule deer,

is much harder to deal with. Two years ago,

the Centre brought together international

...2

CWD

experts in CWD, disease monitoring, deer biology, and other specialties to help determine

whether CWD in wild deer in Canada represented a potential crisis. They determined that it

does.

“They told us Canada had a few years to develop its response to CWD,” he recalls, “because

this is a slow-moving disease. They recommended that Canada take determined action to

control the disease in wild deer, but warned that there were no proven methods of doing this

and that scientific research carried out in the affected areas would have to guide any effective

response. They emphasized that there would be large social, ecological or economic

consequences for Canada if we do not stop the spread of CWD in wild deer.”

Dr. Leighton praises the foresight that led to PrioNet’s creation, and the flexibility the network

has been given to deal with a disease that was, until recently, overshadowed by BSE concerns in

Canada. “Our priority with respect to CWD is to learn as much as we can about how it is

transmitted. Only then can we develop a program to contain and eliminate it.” •

Coming Together

PrioNet established its Student and

Young Professional Association

(SYPA) at its recent Annual General

Meeting 2006. Joel Watts and Qasim

Khan (University of Toronto) are

SYPA’s interim leaders.

SYPA includes graduate students,

post-doctoral fellows, research associates,

and research technicians who

are involved with PrioNet’s network

investigators. The purpose of this

association is to organize studentfocused

events; liaise with PrioNet

regarding issues surrounding students

and young professionals; and work

together to capitalize on the different

programs PrioNet has available to

strengthen their research and training

experience.

PrioNet will be implementing a variety

of education and training programs to

facilitate learning exchange and enrich

the experience of students and young

professionals within the network. For

resources such as job postings and

training updates related to students

and young professionals, visit the Education

and Training link at

www.prionetcanada.ca. •

PrioNet’s Research Projects Related to CWD & BSE

PrioNet Canada will address Canadian prion challenges through its five research themes. The

theme leaders and targeted research projects related to the themes of Bovine Spongiform Encephalopathy

and Chronic Wasting Disease are outlined below:

Research Theme I: Bovine Spongiform Encephalopathy

Theme Leader: Dr. Steven Moore, University of Alberta

Associate Leader: Dr. Mike Belosevic, University of Alberta

Theme Pathologist: Dr. Stefanie Czub, Canadian Food Inspection Agency

A Comprehensive and Comparative Approach to Genetics & Pathobiology of Prion

Disease

Principal Investigator: Dr. Steven Moore, University of Alberta

Co-Investigators:

Dr. John Williams, Parco Tecnologico Padano, Italy

Dr. Michael Coulthart, Public Health Agency of Canada

Dr. Denny Crews, Agriculture & Agri-food Canada

Dr. Stefanie Czub, Canadian Food Inspection Agency

Dr. Michael Heaton, US Department of Agriculture

Prion Inactivation and Environment

Principal Investigator: Dr. Mike Belosevic, University of Alberta

Co-Investigators:

Dr. Norman Neumann, University of Calgary

Dr. Neil Cashman, University of British Columbia

Dr. Daniel Smith, University of Alberta

Dr. Steven Craik, University of Alberta

Dr. Mohamed Gamal El-Din, University of Alberta

Dr. Phillip Fedorak, University of Alberta

Immunoprophylaxis of Bovine Spongiform Encephalopathy

Principal Investigator: Dr. Andrew A. Potter, University of Saskatchewan

Co-Investigators:

Dr. Philip Griebel, University of Saskatchewan

Dr. Scott Napper, University of Saskatchewan

Dr. Lorne Babiuk, University of Saskatchewan

Research Theme II: Chronic Wasting Disease

Theme Leader: Dr. Ted Leighton, University of Saskatchewan

Associate Theme Leader: Dr. Cheryl Waldner, University of Saskatchewan

Sub-Theme Leader (for Scrapie): Dr. Aru Balachandran, Canadian Food Inspection Agency

Factors Affecting Prevalence and Geographic Spread of Chronic Wasting Disease in

Wild Deer in Saskatchewan (Phase I & II)

Principal Investigator: Dr. Trent Bollinger, University of Saskatchewan

Co-Investigators:

Dr. Dave Coltman, University of Alberta

Dr. Ted Leighton, Canadian Cooperative Wildlife Health Centre, University of Saskatchewan

Dr. Francois Messier, University of Saskatchewan

Dr. Cheryl Waldner, Western College of Veterinary Medicine, University of Saskatchewan

A Comparative Approach Examining Host Response to TSE Infection by Serial Analysis

of Gene Expression (microSAGE) in Cervids and Ovids

Principal Investigator: Dr. Stephen Moore, University of Alberta

Co-Investigators:

Dr. Michael Brownstein, J. Craig Venter Institute

Dr. Mike Miller, Wildlife Research Centre, Colorado

Dr. Catherine Graham, Canadian Food Inspection Agency

Dr. Aru Balachandran, Canadian Food Inspection Agency

PrioNet’s Research Projects Related to CWD & BSE

PrioNet Canada will address Canadian prion challenges through its five research themes. The

theme leaders and targeted research projects related to the themes of Bovine Spongiform Encephalopathy

and Chronic Wasting Disease are outlined below:

Stay tuned to upcoming

issues of PrioNews as

we feature PrioNet’s

three other research

themes:

==================================END

DNA polymorphisms of the prion doppel gene region in four different German
cattle breeds and cows tested positive for bovine spongiform encephalopathy

Journal Mammalian Genome
Publisher Springer New York
ISSN 0938-8990 (Print) 1432-1777 (Online)
Subject Biomedical and Life Sciences and Medicine
Issue Volume 16, Number 11 / November, 2005
DOI 10.1007/s00335-005-0052-9
Pages 884-892
Online Date Saturday, November 12, 2005


N. Balbus1, A. Humeny1, K. Kashkevich1, I. Henz1, C. Fischer2, C.-M. Becker1
and K. Schiebel1

(1) Institut für Biochemie, Emil-Fischer-Zentrum, Universität
Erlangen-Nürnberg, Fahrstrasse 17, 91054 , Erlangen, Germany
(2) Institut für Humangenetik, Universität Heidelberg, Im Neuenheimer Feld
366, 69120, Heidelberg, Germany

Received: 5 April 2005 Accepted: 18 July 2005 Published online: 11
November 2005

Abstract Polymorphisms of the prion protein gene PRNP have been shown to
influence the susceptibility/resistance to prion infections in human and
sheep. In addition, the T174M polymorphism within the flanking prion doppel
gene (PRND) was thought to be involved in susceptibility to sporadic
Creutzfeldt-Jacob disease. To study a possible influence of DNA
polymorphisms of the bovine PRND gene in bovine spongiform encephalopathy
(BSE), previously identified and newly isolated DNA polymorphisms were
genotyped in all available German cattle that tested positive for BSE.
Genotypes and calculated haplotypes were compared with breeding bulls
serving as controls. Analysis of the four major breeds Schwarzbunt (Holstein
Friesian), Rotbunt (Holstein Red), Fleckvieh (Simmental), and Braunvieh
(Swiss Brown) resulted in the isolation of the previously known
polymorphisms R50H and R132Q and two novel synonymous single nucleotide
polymorphisms (SNPs) C4820T and A5063T. Comparative genotype and haplotype
analysis of BSE and control animals revealed a significantly different
distribution of polymorphisms C4815T and R132Q in Fleckvieh animals but not
in the other breeds tested. No association to BSE susceptibility was
detectable for polymorphisms R50H and A5063T.

----------------------------------------------------------------------------
----


K. Schiebel
Email: katrin.schiebel@biochem.uni-erlangen.de
Phone: 49-9131 85-26206
Fax: 49-9131 85-22485

References secured to subscribers.


http://www.springerlink.com/content/y1222u1n55756w18/?p=9b0ad07fa1564bfba3e9c382a5cabec8&pi=7


Subject: Atypical BSE in Germany-Proof of transmissibility and biochemical
characterization
Date: August 20, 2006 at 3:33 pm PST
Copyright © 2006 Elsevier B.V. All rights reserved.

Atypical BSE in Germany-Proof of transmissibility and biochemical
characterization


A. Buschmanna, A. Gretzschela, A.-G. Biacabeb, K. Schiebelc, C. Coronad, C.
Hoffmanna, M. Eidena, T. Baronb, C. Casaloned and Martin H. Groschupa, ,

aFriedrich-Loeffler-Institut (FLI), Institute for Novel and Emerging
Infectious Diseases, Boddenblick 5a, 17493 Greifswald, Insel Riems, Germany
bAFSSA-Lyon, Unite ATNC, Lyon, France
cInstitut für Biochemie, Universitity Erlangen-Nürnberg, Germany
dCEA, Instituto Zooprofilattico di Turino, Turin, Italy

Received 11 January 2006; revised 23 May 2006; accepted 2 June 2006.
Available online 17 August 2006.

Abstract


Intensive active surveillance has uncovered two atypical German BSE cases in
older cattle which resemble the two different atypical BSE phenotypes that
have recently been described in France (designated H-type) and Italy
(designated L-type or BASE). The H-type is characterized by a significantly
higher molecular size, but a conventional glycopattern of the proteinase K
treated abnormal prion protein (PrPSc), while the L-type PrPSc has only a
slightly lower molecular size and a distinctly different glycopattern. In
this paper we describe the successful transmission of both German atypical
BSE cases to transgenic mice overexpressing bovine PrPC. Upon challenge with
the L-type, these mice developed BSE after a substantially shorter
incubation period than any classical BSE transmission using these mice to
date. In contrast, the incubation period was distinctly prolonged when these
mice were challenged with the H-type. PrPSc accumulated in the brains of
these mice were of the same atypical BSE type that had been used for the
transmission. These atypical cases suggest the possible existence of
sporadic BSE cases in bovines. It is thus feasible that the BSE epidemic in
the UK could have also been initiated by an intraspecies transmission from a
sporadic BSE case.

Keywords: BSE; Cattle; PrPSc; Biochemical differentiation


http://www.sciencedirect.com/

THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 280, NO. 45, pp. 37408–37414, November 11, 2005

© 2005 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in the U.S.A.

Bovine Prion Protein Gene (PRNP) Promoter Polymorphisms

Modulate PRNP Expression and May Be Responsible for

Differences in Bovine Spongiform Encephalopathy

Susceptibility*□S

Received for publication, June 10, 2005, and in revised form, July 20, 2005 Published, JBC Papers in Press, September 1, 2005, DOI 10.1074/jbc.M506361200

Petra Sander‡, Henning Hamann‡, Cord Dro¨gemu¨ ller‡, Kseniya Kashkevich§, Katrin Schiebel§, and Tosso Leeb‡1

From the ‡Institute for Animal Breeding and Genetics, University of Veterinary Medicine, Bu¨nteweg 17p, 30559 Hannover, Germany

and the §Institute for Biochemistry, University of Erlangen-Nu¨rnberg, Fahrstrasse 17, 91054 Erlangen, Germany

The susceptibility of humans to the variant Creutzfeldt-Jakob

disease is greatly influenced by polymorphisms within the human

prion protein gene (PRNP). Similar genetic differences exist in

sheep, in which PRNP polymorphisms modify the susceptibility to

scrapie. However, the known coding polymorphisms within the

bovine PRNP gene have little or no effect on bovine spongiform

encephalopathy (BSE) susceptibility in cattle. We have recently

found a tentative association between PRNP promoter polymorphisms

and BSE susceptibility in German cattle (Sander, P.,

Hamann, H., Pfeiffer, I., Wemheuer, W., Brenig, B., Groschup, M.,

Ziegler, U., Distl, O., and Leeb, T. (2004) Neurogenetics 5, 19–25).A

plausible hypothesis explaining this observation could be that the

bovine PRNP promoter polymorphisms cause changes in PRNP

expression that might be responsible for differences in BSE incubation

time and/or BSE susceptibility. To test this hypothesis, we performed

a functional promoter analysis of the different bovine PRNP

promoter alleles by reporter gene assays in vitro and by measuring

PRNPmRNAlevels in calves with different PRNP genotypes in vivo.

Twovariable sites, a 23-bp insertion/deletion (indel) polymorphism

containing a RP58-binding site and a 12-bp indel polymorphism

containing an SP1-binding site, were investigated. Band shift assays

indicated differences in transcription factor binding to the different

alleles at the two polymorphisms. Reporter gene assays demonstrated

an interaction between the two postulated transcription factors and

lower expression levels of the ins/ins allele compared with the del/del

allele. The in vivo data revealed substantial individual variation of

PRNP expression in different tissues. In intestinal lymph nodes,

expression levels differed between the different PRNP genotypes. ...SNIP...END...TSS



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